Guidelines for the diagnosis and treatment of follicular lymphoma in China

Follicular lymphoma (FL) is a common type of nonHodgkin’s lymphoma (NHL), accounting for 22% to 35% of NHL in western countries. The proportion in China, 8.1% to 23.5%, is less than that in western countries, although its incidence in China has increased with time. Compared with foreign countries, the age of onset is younger in China, and in terms of geographical distribution, the incidences in coastal regions and economically developed areas are higher 1 -3 . FL is from germinal-center B-cells, and is manifested morphologically as a tumor retaining follicular growth. FL comprises a group of malignant lymphoproliferat ive diseases including follicular center cells (small cleaved cells) and follicular center matricytes (large non-cleaved cells). Under microscopy, FL sometimes appears to be associated with diffused components. Based on different follicular components and their proportions, FL can be divided into the following (1) follicle-dominant type (proportion of follicles >75%); (2) follicle and diffuse mixed type (follicles accounting for 25% to 75%); and (3) focal follicle (proportion of follicles <25%)

can facilitate diagnosis.

Inspection, staging, and prognosis of FL
The diagnostic test of FL is similar to other indolent lymphoma inspections. The necessary steps include the following: general physical examination, particularly to check if superficial lymph node, liver, and spleen are enlarged; laboratory examination, including complete blood cell inspection, blood biochemical inspection, as well as serum lactate dehydrogenase (LDH) level, hepatitis B and C, and HIV-related detection; and imaging examinations via enhanced computed tomography (CT) detection of neck, chest, abdomen, and pelvic cavity and via bilateral or unilateral bone marrow biopsy plus smear examination, which are recommended to be performed routinely. The sample for bone marrow biopsy should be at least larger than 1.6 cm. Using positron emission tomography (PET)/ CT is helpful in detecting some non-palpable lesions, but its clinical value is lower than those found in DLBCL and Hodgkin's lymphoma subtype. In addition, PET/CT can help diagnose FL transformation.
To predict FL prognosis, the standard of FL International Prognosis Index (FLIPI) is as follows: for FLIPI-1, age ≥60, Ann Arbor staging includes stages III to IV, hemoglobin (HBG) <120 g/L, serum LDH >upper limit of normal range, and involved lymph nodes ≥5. Each indicator refers to a score of 1. According to the scores, FL patients can be divided into three risk groups, namely, low risk, intermediate risk, and high risk. In recent years, with the increasingly common use of IDEC-C2B8 (rituximab) for treating FL, the new clinical prognostic scoring system, FLIPI-2, is considered an improved version of FLIPI-1. FLIPI-2 includes the following factors: β 2 -microglobulin > upper limit of normal range, maximal lymph node diameter>6 cm, bone marrow being violated, HGB <120 g/L, and age >60 ( Table 1).

Treatment of FL Treatment indicators
Localized radiation therapy is mainly adopted for FL patients in Stages I and II. The disease-free survival is extended for most patients. Therefore, radiation therapy or radiation therapy associated with general immunochemotherapy should be adopted as soon as possible.
Currently, FL patients in Stage II with abdominal mass and Stages III to cannot be cured with the available treatment methods. Most patients have slow disease progression and can maintain better quality of life, even if treatment is not for a long time. Thus, a patient can be treated if one of the following treatment indicators is exhibited ( Table 2).
The following items should be detected before treatment: (1) disease history; (2) physical examination aimed at identifying possible areas of lymph node accumulation and the sizes of the cerebral arterial circle and liver and spleen; (3) physical condition; (4) B symptoms; (5) complete blood count and biochemical routine; (6) CT scans of the neck, chest, abdomen, and pelvis; (7) hepatitis B virus detection; (8) bone marrow biopsy and smear; (9) routine electrocardiogram.
Ultrasonic cardiogram of the left ventricular ejection fraction, PET/CT, β 2 -microglobulin, uric acid, serum protein electrophoresis, and/or quantitative immunoglobulins and Hepatitis C-related examination can also be performed, if necessary.

Front-line treatment options of FL patients in Stages I to II
FL patients in level 3 should be treated based on DLBCL treatment strategy. Enough clinical evidence has shown that involved field radiation therapy (IFRT) is an ideal treatment option for FL patients in stages I to II of levels 1 and 2. Improved long-term survival rate can be achieved by simple radiation treatment, with a radiation dose of 30 Gy to 36 Gy. Although the efficacy of general immunochemotherapy associated with the radiation treatment for FL patients in Stages I to II has yet to be fully explored, several reports have pointed out that such treatment could improve survival. Watchful monitoring is recommended if the risk of adverse reactions of FL patients for IFRT is estimated to be greater than the probability of clinical benefits. Front-line-associated immunochemotherapy may be recommended for patients in Stages I to II with high tumor burden or patients in FLIPI intermediate and high risk (>1 score) 8 .

Front-line treatment of FL patients in Stages III to IV
Compared with FL in Stages I to II, FL in Stages III to IV is generally considered an incurable disease. The watchful monitoring strategy can be adopted if patients have no treatment indicators ( Table 2). For FL patients in Stages III to IV with treatment indicators, the treatment options are more current, and the general principle is to choose a highly individual treatment program based on age, general physical conditions, complications, and treatment goal.
Immunochemistry is currently the most commonly selected treatment mode at home and abroad. The treatment program with 8 courses of rituximab associated with chemotherapy has become the preferred standard program at home and abroad for the initial treatment of FL patients. Regardless of which treatment is chosen (i.e., CHOP, CVP program, or fludarabine associated with rituximab), all treatment methods have been shown to improve recent and long-term effects significantly, including overall survival. Therefore, routine dose of associated chemotherapy plus rituximab is suggested for relatively young patients with better constitution 9,10 .
Meanwhile, researchers have still not reached a consensus on the optimal front-line treatment program for late-stage FL patients, either by chemotherapy associated with rituximab or single-agent rituximab. Nevertheless, the result of a recent FOLL05 experiment shows that R-CHOP program is better than R-CVP or R-FM program based on risks and benefits. Several studies have shown that fludarabine has toxicity on bone marrow stem cells and is related to secondary tumor. Therefore, premature use should be avoided, particularly for patients with autologous hematopoietic stem cell transplantation (ASCT).
For weak and old patients who are unable to endure combination chemotherapy, single-agent rituximab, singleagent chemotherapy, or rituximab associated with single-agent chemotherapy can be selected for front-line treatment. In addition, supportive treatment should be enhanced.

The treatment rule of relapsed FL patients
Regardless of the type of induced immunochemotherapy adopted, relapse can occur after a period of disease remission. As of this writing, the standard treatments for relapsed, intractable FL patients have yet to be unified. The option for salvage therapy depends on the curative effects of previous programs, release time, age of patients, physical conditions, pathologic types at relapse, and treatment goal. For the relapsed patients without transformation and with long-term remission after front-line treatment, the original program or other front-line programs can be used. For the early relapsed patients (<12 months), noncross drug-resistant program (e.g. fludarabine, can be used as salvage program if relapse occurs after CHOP treatment) can be selected and applied. The effective rate of rituximab for treating relapsed FL is around 45%, whereas the rate for CR is 6%. Rituximab can also increase the effect of salvage chemotherapy. The salvage chemotherapy options include CHOP, fludarabinebased program, CVP, and radioimmunotherapy. New drugs and new combined programs can also be considered. Thus, it is recommended that ASCT be adopted in the treatment of relapsed young patients 9,10 .

Maintenance treatment of FL
FL patients with a long disease history and slow progress are more sensitive to various treatments. Thus, maintenance treatment is suitable for these patients after remission induction. Numerous clinical studies and meta-analysis results have proven that, for FL patients after front-line treatment or one more remission induction of relapse, the maintenance treatment via single-agent rituximab improves long-term survival 11 -14 . Therefore, the recommended treatment for patients being initially treated or relapsed patients after induction chemotherapy and complete remission (CR) or partial remission (PR) is one maintenance treatment by single-agent rituximab every 2 to 3 months, for a total of 2 years. However, the probability of infection can increase after maintenance treatment. Close follow-up and observation should be given to hepatitis B patients 15 .

Treatment of conversion FL lymphoma
Around 20% to 70% of FL that occur in patients can be clinically transformed into other more invasive lymphomas. The most common of these invasive lymphomas is DLBCL, which has an annual incidence rate of 2% to 3% and has continued to increase for at least 15 years. After this period, the transformation risk decreases gradually, after which the transformation is no longer affected regardless of whether or not FL patients have ever been treated. Most patients, after undergoing transformation, have poor prognosis, with a median survival time of 10 to 18 months. Uneven values in FDG-PET scanning and increasing standardized uptake value can show the transformation, which should be verified by biopsy. Currently, no standard therapeutic measure exists for transformative FL; thus, the therapeutic measure of transformed invasive lymphoma can be adopted. The patients treated by mild chemotherapy or those who have not recieved chemotherapy can choose anthracycline-based combined chemotherapy ± radiation treatment or chemotherapy ± rituximab, in order to achieve better outcome. If patients have been previously treated strongly by numerous kinds of chemotherapy programs, IFRT or other chemotherapy programs can be considered. These patients with poor prognosis are recommended to participate in clinical trials. If patients are sensitive to chemotherapy, hematopoietic stem cell transplantation, particularly ASCT, should be considered for administration after they are eased again into treatment. Meanwhile, allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be attempted in a small number of highly selected patients.

Hematopoietic stem cell transplantation
The therapeutic action of high-dose chemotherapy supported by ASCT on FL patients in Stages III to IV remains controversial. Various studies have shown that ASCT is not highly effective for patients being eased initially, and that autologous transplantation can extend the survival time of FL patients with sensitive relapse (1 to 4 relapses by preference). Therefore, FL patients in Stages III to IV who are still sensitive to chemotherapy after numerous relapses are encouraged to participate in such kind of clinical trial, especially if they are young or have good physical conditions with improved function of vital organs. With the continuous progress of allo-HSCT, myeloablative or non-myeloablative allo-HSCT have initially shown long-term survival benefits for several patients. However, the problem of high transplantation-related mortality rate still needs to be solved. Currently, allo-HSCT is only suitable for a small number of patients for research.

Treatment of untoward effects
Details are found in the relative treatment guidelines of DLBCL in China.

Follow-up
Follow-up must be conducted every 2 to 3 months in the first year for patients in remission stage (CR or PR) after all treatment methods. Then, one follow-up every 3 months should be conducted in the second year, followed by one follow-up every 6 months. The follow-up sessions may also be scheduled according to clinical indications. Follow-up content covers repeat diagnostic test, imaging examination based on the clinical situations (i.e., depending on disease region and clinical feature), and physical examination.